Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

Weyburne, Emily S.; Wilkins, Owen M.; Sha, Zhe; Williams, David A.; Pletnev, Alexandre A.; Bruin, Gerjan de; Overkleeft, Hermann S.; Goldberg, Alfred L.; Cole, Michael; Kisselev, Alexei F.

doi:10.1016/j.chembiol.2016.12.016

Cited by 99 publications

(114 citation statements)

References 49 publications

(82 reference statements)

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“…It can be constitutive (20S) or immunological (20Si); both forms have the same beginning. The expression of the 26S proteasome is directly linked to transcription factor Nrf1, and inhibition of Nrf1 was recently shown to suppress the 26S proteasome by Weyburne et al [29]. The assembly of the proteasome is overseen mainly by two pairs of proteasome-assembling chaperone (PAC) facilitators, PAC1-PAC2 and PAC3-PAC4.…”

Section: Introductionmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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Section: Introductionmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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“…In general, the β 5 subunits are the most important ones in protein degradation and are treated as the main targets for inhibitors. It is worth noting however, that significantly higher antitumor response can be achieved if the second active subunit— β 1 or β 2—is coinhibited . Mirabella et al .…”

Section: Resultsmentioning

confidence: 99%

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

et al. 2018

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The conversion of primary structures of novel, highly selective and sensitive, internally quenched peptide substrates of the human 20S proteasome into peptide aldehydes is presented. Such covalent and reversible inhibitors differ in their primary structures and chemical moieties attached to their N‐terminal amino group. Inhibitory potency is primarily tested against proteolytic subunits of human constitutive 20S proteasome (β1c, β2c, and β5c subunits), but in some cases, also against 20S immunoproteasome β5i. Most of the peptide aldehydes act nonspecifically and bind equipotently to the corresponding proteolytic subunits of both forms of proteasome (β5c and β5i). Two inhibitors are 2.7‐times more specific for immunoproteasome over its constitutive counterpart. The antitumor activity of the selected inhibitors and MG132 (used here as the reference) is analyzed using MTT assay against nonmalignant human fetal osteoblastic hFOB 1.19, malignant human osteosarcoma MG‐63, human pancreatic cancer MiaPaCa‐2, and human acute leukemia Jurkat T cell lines. All inhibitors tested are able to decrease cell viability in a concentration‐dependent manner. One of the peptide aldehydes exerted stronger, as compared to the MG132, activity against human glioblastoma cell line U87‐MG. Moreover, its combination with dinaciclib, which is a novel, potent inhibitor of cyclin‐dependent kinases, reduces cellular metabolic activity more potently as compared to either proteasome inhibitor or dinaciclib alone.

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“…These potent inhibitors of the β5 peptidase activity of the 26S proteasome have only modest activity against β1 and β2 peptidases, which appears to limit their usefulness to multiple myeloma [146]. The β5 peptidase inhibitors have not been successful in treatment of solid tumors, and in recent studies triple negative breast cancer cell lines only responded to bortezomib or carfilzomib after CRISPR gene editing to inactivate β2 [147]. Development of dual β2/β5 inhibitors, while conceptually attractive, may prove daunting, and combination therapy with the β5 and known β2 inhibitors is a more realistic approach.…”

Section: Proteases and Diseasementioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

Cited by 99 publications

References 49 publications

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

Proteases: Pivot Points in Functional Proteomics

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